The amount of bone remodeling in the skeleton has been associated with fracture risk independent of clinical measures of bone mineral density. This has led to the suggestion that bone remodeling can influence bone fragility independent of bone mass. Although many explanations have been proposed, it is currently not known how bone remodeling alone can influence bone strength independent of bone mass. In this work we evaluate the most commonly cited explanation for the effect of bone remodeling on bone strength: that cavities formed during the remodeling process (resorption cavities) act as microstructural flaws or stress risers. Resorption cavities may influence cancellous bone stiffness and strength under a single load or may lead to reductions in cancellous bone strength or stiffness by promoting the initiation and/or propagation of microscopic cracks and other tissue damage. This project is based on the hypothesis that resorption cavities impair bone stiffness and strength independent of bone mass. The specific aims are to 1) determine how the number and morphology of resorption cavities influence the bone stiffness and strength of human cancellous bone and the degree to which resorption cavities are associated with microscopic tissue damage caused by a single loading event; 2) determine if microscopic tissue damage caused by a single overloading event impairs cancellous bone strength under reloading; 3) determine how microscopic tissue damage formed during cyclic loading is associated with reductions in cancellous bone stiffness; and 4) determine if resorption cavities promote the initiation or propagation of microscopic cracks during cyclic loading. Completing these aims will provide a quantitative evaluation of the most commonly cited explanation for the relationship between bone turnover and fracture risk. PUBLIC HEALTH RELEVANCE: This project addressed the problem of osteoporosis-related fractures in the elderly by determining how measures of biological activity in the skeleton (bone remodeling) are related to the ability of bone to resist fracture. The proposed research has the potential to influence clinical decisions regarding the treatment and prevention of osteoporosis.